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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
- Mattila, Tiina M., et al.
(författare)
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Genetic continuity, isolation, and gene flow in Stone Age Central and Eastern Europe
- 2023
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The genomic landscape of Stone Age Europe was shaped by multiple migratory waves and population replacements, but different regions do not all show similar patterns. To refine our understanding of the population dynamics before and after the dawn of the Neolithic, we generated and analyzed genomic sequence data from human remains of 56 individuals from the Mesolithic, Neolithic, and Eneolithic across Central and Eastern Europe. We found that Mesolithic European populations formed a geographically widespread isolation-by-distance zone ranging from Central Europe to Siberia, which was already established 10,000 years ago. We found contrasting patterns of population continuity during the Neolithic transition: people around the lower Dnipro Valley region, Ukraine, showed continuity over 4000 years, from the Mesolithic to the end of the Neolithic, in contrast to almost all other parts of Europe where population turnover drove this cultural change, including vast areas of Central Europe and around the Danube River. Genome-wide sequencing of 56 ancient hunter-gatherer and early farmer individuals from Stone Age Central and Eastern Europe reveals striking population continuity in the east in contrast to central Europe that displays extensive admixture.
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| 4. |
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| 5. |
- Günther, Torsten, et al.
(författare)
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Population genomics of Mesolithic Scandinavia : Investigating early postglacial migration routes and high-latitude adaptation
- 2018
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Scandinavia was one of the last geographic areas in Europe to become habitable for humans after the Last Glacial Maximum (LGM). However, the routes and genetic composition of these postglacial migrants remain unclear. We sequenced the genomes, up to 57x coverage, of seven hunter-gatherers excavated across Scandinavia and dated from 9,500-6,000 years before present (BP). Surprisingly, among the Scandinavian Mesolithic individuals, the genetic data display an east-west genetic gradient that opposes the pattern seen in other parts of Mesolithic Europe. Our results suggest two different early postglacial migrations into Scandinavia: initially from the south, and later, from the northeast. The latter followed the ice-free Norwegian north Atlantic coast, along which novel and advanced pressure-blade stone-tool techniques may have spread. These two groups met and mixed in Scandinavia, creating a genetically diverse population, which shows patterns of genetic adaptation to high latitude environments. These potential adaptations include high frequencies of low pigmentation variants and a gene region associated with physical performance, which shows strong continuity into modern-day northern Europeans.
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| 6. |
- Svensson, Emma, 1979-, et al.
(författare)
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Genome of Pesxtera Muierii skull shows high diversity and low mutational load in pre-glacial Europe
- 2021
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Ingår i: Current Biology. - : Cell Press. - 0960-9822 .- 1879-0445. ; 31:14, s. 2973-U21
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Tidskriftsartikel (refereegranskat)abstract
- Few complete human genomes from the European Early Upper Palaeolithic (EUP) have been sequenced. Using novel sampling and DNA extraction approaches, we sequenced the genome of a woman from "Pesxtera Muierii,"Romania who lived similar to 34,000 years ago to 13.5x coverage. The genome shows similarities to modern-day Europeans, but she is not a direct ancestor. Although her cranium exhibits both modern human and Neanderthal features, the genome shows similar levels of Neanderthal admixture (similar to 3.1%) to most EUP humans but only half compared to the similar to 40,000-year-old Pesxtera Oase 1. All EUP European hunter-gatherers display high genetic diversity, demonstrating that the severe loss of diversity occurred during and after the Last Glacial Maximum (LGM) rather than just during the out-of-Africa migration. The prevalence of genetic diseases is expected to increase with low diversity; however, pathogenic variant load was relatively constant from EUP to modern times, despite post-LGM hunter-gatherers having the lowest diversity ever observed among Europeans.
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| 7. |
- Domínguez-Andrés, Jorge, et al.
(författare)
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Evolution of cytokine production capacity in ancient and modern European populations
- 2021
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- As our ancestors migrated throughout different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits that influence the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.
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| 8. |
- Ferwerda, Bart, et al.
(författare)
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Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:25, s. 10272-10277
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Tidskriftsartikel (refereegranskat)abstract
- Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
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| 9. |
- Koeken, Valerie A. C. M., et al.
(författare)
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The effect of BCG vaccination on alveolar macrophages obtained from induced sputum from healthy volunteers
- 2020
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Ingår i: Cytokine. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 1043-4666 .- 1096-0023. ; 133
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Tidskriftsartikel (refereegranskat)abstract
- The anti-tuberculosis vaccine Bacillus Calmette-Guerin (BCG) is able to boost innate immune responses through a process called trained immunity. It is hypothesized that BCG-induced trained immunity contributes to protection against Mycobacterium tuberculosis infection. Since alveolar macrophages are the first cell type to encounter M. tuberculosis upon infection, we aimed to investigate the immunomodulatory effects of BCG vaccination on alveolar macrophages. Searching for a less-invasive method than bronchoalveolar lavage, we optimized the isolation of alveolar macrophages from induced sputum of healthy volunteers. Viable alveolar macrophages could be successfully isolated from induced sputum and showed signs of activation already upon retrieval. Further flow cytometric analyses revealed that at baseline, higher expression levels of activation markers were observed on the alveolar macrophages of smokers compared to non-smokers. In addition, BCG vaccination resulted in decreased expression of the activation markers CD11b and HLA-DR on alveolar macrophages. Future studies should evaluate the functional consequences of this reduced activation of alveolar macrophages after BCG vaccination.
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| 10. |
- McCall, Matthew B B, et al.
(författare)
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Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations
- 2010
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Ingår i: European Cytokine Network. - 1148-5493 .- 1952-4005. ; 21:2, s. 77-83
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Tidskriftsartikel (refereegranskat)abstract
- Background. The full-length (L-) variant of caspase-12 is believed to predispose to sepsis. It has been replaced in the genome of most human populations by the (S-) variant, which leads to premature termination of translation. Strikingly, the L-allele is still widely prevalent in African populations, presumably due to a counterbalancing selective force specific to this continent, for which malaria is a prime candidate.Methods. We investigated associations between caspase-12 genotype and malarial parameters in three West-African populations, in studies encompassing immunological, clinical and obstetric data. Results. The caspase-12 L-allele was found at frequencies of 11-34%. Plasmodium falciparum-stimulated mononuclear cells from S/L heterozygote donors produced stronger interferon-γ and interleukin-10 responses than S/S homozygotes (p = 0.011 and p = 0.023 in uninfected and infected donors respectively). Nevertheless, we found no association between caspase-12 genotype and either the presentation of severe malaria or individual clinical parameters in sick children. Amongst pregnant women, the caspase-12 genotype did not influence peripheral or placental malaria infection, or basic obstetric parameters. Interestingly, perinatal mortality was more frequent in children of both S/S and L/L than S/L mothers, independent of placental P. falciparum-infection.Conclusion. We find little clinical or epidemiological evidence that malaria has contributed to the persistence of functional caspase-12 in Africa, suggesting either that alternative selective forces are at work or that genetic drift underlies its current global distribution.
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